Stable aqueous compositions comprising bioactive creatine species

ABSTRACT

Compositions containing one or more bioactive forms of creatine, which are aqueous compositions in which the one or more bioactive forms of creatine do not appreciably degrade into creatinine. Also are methods for providing various beneficial effects which comprise administering aqueous compositions comprising at least one creatinol O-phosphate species to a mammalian subject, either chronically or acutely.

CROSS-REFERENCE TO A RELATED APPLICATION

This application is a continuation application of application Ser. No.12/138,984, filed Jun. 13, 2008, now U.S. Pat. No. 8,372,821; whichclaims the benefit of U.S. provisional application Ser. No. 61/043,619,filed Apr. 9, 2008, both of which are hereby incorporated by referencein their entirety.

TECHNICAL FIELD

This disclosure relates generally to stable aqueous solutions ofcreatine, methods for their preparation and methods of use.

BACKGROUND OF THE INVENTION

Many nutritional supplements are available at various retail outlets, inmany forms, including pills, powders, and liquids intended for humanconsumption.

One nutritional supplement that has become popular is creatine, whoseIUPAC name is 2-(carbamimidoyl-methyl-amino) acetic acid, (CAS No.57-00-1). Creatine occurs naturally in muscle and is believed to be anessential component in energy-producing metabolism and normal musclefunction and growth. It is also believed by many to be useful tobodybuilders for increasing muscle mass, i.e., muscle-building.

Creatine is typically offered in powder, pill or capsule form. However,no aqueous-based formulations containing appreciable amounts ofcreatine, intended for oral human consumption, are readily available inthe marketplace. This is because creatine is unstable in aqueoussystems, in which it rearranges to creatinine. Creatinine is thebreakdown product of creatine; creatinine has no effect on muscleprotein

BRIEF SUMMARY

The subject invention provides stable aqueous compositions of at leastone biologically-active form of creatine. In a preferred embodiment, thecompositions of the subject invention comprise:

-   a) at least one creatinol-O-phosphate (COP) species; and-   b) water.

Advantageously, these compositions are stable across a wide range of pHsand temperatures. These formulations may have, for example, a pH of fromabout 3 to about 7 or more, and are stable at temperatures between 4° C.(or less) and 40° C. (or more). Advantageously, across this wide rangeof conditions, the concentration of bioactive species in thesecompositions does not decrease appreciably over periods of 40 or even 60days or more.

The compositions of the subject invention may further comprise one ormore additional materials selected from, for example, flavoring agents,colorants, viscosity modifiers, preservatives, fragrances, amino acidsand their salts, vitamins, minerals, essential fatty acids, enzymes,co-enzymes, mono-glycerides, di-glycerides, tri-glyceride ester oilsemulsifiers, hydrolyzed proteins, whey protein, stabilizers, flowmodifiers, viscosity improvers, chelating agents, anti-oxidants,anti-microbials, benzoates, alcohols, esters of para-hydroxybenzoicacid, propionates, preservatives and surfactants.

The subject invention further provides methods for preparing and usingthese compositions.

The compositions of the subject invention can provide any one or more ofwide range of physiological benefits including regeneration of ADP toATP in muscle tissue, increasing the serum concentration of creatine,causing an increase in the skeletal muscle concentrations of creatineand phosphocreatine (PCr), increasing muscle fiber size/cross-sectionalarea and lean body mass, activating satellite cells, enhancing memoryand cognitive function, enhancing the functional capacity of a mammalhaving a neuromuscular disease, increasing muscular strength, enduranceand/or power, enhancing cognitive function in infants with inborn errorsof creatine metabolism, and/or alleviating the deleterious effects ofsleep deprivation.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a graph that charts the increase in creatinine levels insolutions of various creatine salts over time. The solutions wereprepared at pH 3 (Acid), and pH 7 (Neutral) conditions and were storedat room temperature (25° C.), and assayed by High Performance LiquidChromatography immediately after preparation, and at several timeintervals thereafter. These results indicate that while other creatinesalts rapidly degrade, creationol-phosphate is stable and resistant todecomposition and even more stable at neutral pH condition.

Result is given by milligram (mg) of creatinine present in ML(milliliters) of solution.

CM-325=Creatine Monohydrate at pH 3.0 and storage at 25° Celsius.

DCTP-3-25=Disodium Creatine Tetraphosphate at pH 3.0 and storage at 25°Celsius.

COP-3-25=Creatinol-O-Phosphate at pH 3.0 and storage at 25° Celsius.

CM-7-25=Creatine Monohydrate at pH 7.0 and storage at 25° Celsius.

DCTP-7-25=Disodium Creatine Tetraphosphate at pH 7.0 and storage at 25°Celsius.

COP-7-25=Creatinol-O-Phosphate at pH 7.0 and storage at 25° Celsius.

DETAILED DESCRIPTION

The subject invention provides stable aqueous compositions of at leastone biologically-active form of creatine. In a preferred embodiment, thecompositions of the subject invention comprise:

a) at least one creatinol-O-phosphate (COP) species; and

b) water.

The subject invention further provides methods for preparing and usingthese compositions.

Specifically exemplified herein are compositions for oral use. Thesubject invention further provides compositions for injection as well asfor topical administration.

In a specific embodiment, the subject invention provides aqueouscompositions of matter suitable for oral administration to mammalsincluding, without limitation, humans.

A composition as provided herein may be administered chronically. Asused herein, “chronically” has its normal meaning, which generally meansrepeated ingestion over a period of several days, several weeks or evenseveral months or more. Acute administration may also be utilized.

Specifically exemplified herein are compositions that comprise one ormore forms of creatinol-O-phosphate (COP) (CAS No. 6903-79 3).Creatinol-O-phosphate is available in commercial quantities from VitalPharmaceuticals, Inc., d/b/a VPX/Redline of Davie, Fla., among othersources. Creatinol-O-phosphate itself has the structure:

MW=197.13and likely exists in a zwitterionic form to some extent. However, evenin such zwitterionic form, one proton remains, which proton can beneutralized using any suitable basic substance including, withoutlimitation, the oxides, hydroxides, caseinates, carboxylates, andcarbonates of alkali metals and alkaline earth metals to afford aqueoussolutions and/or suspensions of salts of creatinol-O-phosphate. Thus,when neutralized with an equimolar amount of a basic compound of amonovalent metal or an amine (including ammonia and alkyl-substitutedamines), a material having the structure:

or a mixture comprising (H) and its zwitterionic form is provided, inwhich examples of M+ may include without limitation such cations as:sodium, lithium, potassium, rubidium, ammonium, any alkyl-substitutedammonium cation, and any other monovalent cation. When neutralized withan equimolar amount of a basic compound of a divalent metal or othercation, a material having the structure:

or a mixture comprising (III) and its zwitterionic form is provided,wherein n equals two, and in which examples of M⁺⁺ may include withoutlimitation such cations as: zinc, calcium, and magnesium and any otherdi-positive cation. The materials described by formulae (I), (II), and(III) above, and the corresponding text in the description, includingany and all of their zwitterionic forms, are all “creatinol-O-phosphatespecies” or “COP species”. The distribution of concentration of theformulae shown above and the zwitterionic forms are pH dependent, asknown to those skilled in the art.

A composition according to this disclosure may be caused to have any pHin the range of between about 1.5 and about 12.5 as desired, byadjusting such compositions using additions of appropriate amounts ofstrong or weak acids or bases including, without limitation, aqueousmineral acids including HCl, H₃PO₄, sodium hydroxide, etc. Preferablythe pH is from about 3.0 to about 7.5.

To prepare a composition according to one embodiment of this invention,a desired amount of creatinol-O-phosphate (or any one or morecreatinol-O-phosphate species) can be added to a selected volume ofwater, and sufficient stirring is effected to cause dissolution of thecreatinol-O-phosphate (or any one or more creatinol-O-phosphate species)to afford an aqueous composition. Furthermore, according to oneembodiment, the solution may be buffered before the addition ofcreatinol-O-phoshate or the solution may be may be made more acidic oralkaline prior to the addition of creatinol-O-phosphate.

According to one embodiment, the total concentration ofcreatinol-O-phosphate species in an aqueous solution provided hereby maybe any amount between about 0.01% and about 20% (or more) by weightbased on the total weight of the aqueous solution, including allpercentages and ranges of percentages therebetween. According to anotherembodiment, the total concentration of creatinol-O-phosphate species inan aqueous solution provided hereby may be any amount between about0.05% and about 7% by weight based on the total weight of the aqueoussolution, including all percentages and ranges of percentagestherebetween. According to another embodiment, the total concentrationof creatinol-O-phosphate species in an aqueous solution provided herebymay be any amount between about 1% and about 5% by weight based on thetotal weight of the aqueous solution, including all percentages andranges of percentages therebetween. In one embodiment,creatinol-O-phosphate (or any one or more creatinol-β-phosphate species)may be added to a natural beverage in any amount provided that anaqueous solution or suspension results.

According to another embodiment, one or more ions selected from thegroup consisting of: sodium, potassium, zinc, calcium, or magnesium(collectively, “metal cations”) are caused to be additionally present inan aqueous solution comprising creatinol-O-phosphate whereincreatinol-O-phosphate is present in any amount as set forth above. Thesemetal cations may be provided by adding a soluble salt or any othermaterial containing any one or more of the metal cations to any aqueoussolution containing one or more of a creatinol-O-phosphate species, ormay be added to water or any aqueous solution prior to addition of oneor more creatinol-O-phosphate species thereto.

The total concentration of these one or more metal cations in acomposition according to this disclosure may be any amount between about0.001% and about 20% by weight based on the total weight of the aqueoussolution, including all percentages and ranges of percentagestherebetween. Such metal ions may derive from a salt or compoundcontaining a creatinol-O-phosphate species, or may derive from otheringredients added to the composition. Such other ingredients include,without limitation, alkali metal halides, alkaline earth metal halides,alkali metal carboxylates, alkaline earth metal carboxylates, and anyother materials known to those skilled in the nutritional arts whichcomprise such metal cations as part of their molecular structure orformula, which are not deleterious to mammalian organisms at theconcentration level at which they are present, which is generally knownin the art.

In addition to ingredients containing one or more metal cations, acomposition according to the subject invention may also includenutritional adjuvant materials including, for example, flavoring agents,colorants, viscosity modifiers, preservatives, fragrances, and othernutritional adjuvant materials. Other nutritional adjuvant materialsinclude any substance that is generally recognized as promoting thehealth or function of a mammalian organism, including humans, orbenefiting a composition useful therefor in terms of either itsefficacy, appearance, stability, consistency, aroma, or viscosity. Suchsubstances include amino acids and their salts, vitamins, minerals,essential fatty acids, enzymes, mono-glycerides, di-glycerides,tri-glyceride ester oils (including, for example vegetable oils andanimal fats) emulsifiers, hydrolyzed proteins, whey protein,stabilizers, flow modifiers, viscosity improvers, chelating agents,enzymes, and surfactants, whether anionic, cationic or nonionic. Thetotal amount of the one or more nutritional adjuvant materials abovepresent in a composition according to this disclosure is present in anyamount between about 0.01% and about 10% by weight based on the totalweight of said composition, including all percentages and ranges ofpercentages therebetween.

In addition to ingredients containing one or more metal cations andother adjuvant materials, a composition according to this disclosure mayalso comprise one or more natural beverages. A natural beverage, as usedherein, is a beverage suitable for human or animal consumption whichcontains the pulp, juice or any other constituent of anaturally-occurring fruit, vegetable, or animal product, whether fromthe wild, cultured, cultivated on a farm or otherwise domesticated.Natural beverages include without limitation materials such as milkproducts, soy products, ice cream, yogurt, citrus fruit juices,non-citrus fruit juices, and vegetable juices, or components of any ofthe foregoing, wherein said natural beverages are present in anyeffective amount to impart flavor to the compositions, which may be anyamount between about 0.1% and about 99% by weight based on the totalweight of said composition, including all percentages and ranges ofpercentages there between.

In addition to ingredients containing one or more metal cations andother adjuvant materials, a composition according to this disclosure mayalternately comprise one or more synthetic beverages. A syntheticbeverage is any beverage which is not a natural beverage.

In general, a composition according to this disclosure may be providedby combining and mixing the ingredients selected, including at least onecreatinol O-phosphate species and any desired quantity of any one ormore other ingredients specified herein. One advantage of compositionsaccording to this disclosure is that they may be packaged at pH levelsas low as about pH 3, in the cold or at about room temperature (22-25°C.) or only slightly elevated temperature (less than, for example, 30°C.), as opposed to many prior art compositions which typically requirehot packaging methods that utilize specialized and expensive equipmentand packaging materials.

Thus, it is evident that a composition according to this disclosure maybe made quite palatable to mammals, including humans. Typical servingsizes may be any serving size in the range of about 1 milligram to about50 grams, in an aqueous solution that is from about 20 ml to about 2500ml in volume. The composition of COP species in an aqueous compositionaccording to this disclosure is limited only by the solubility limit ofthe COP species and concentrations at or near the solubility limit areherein provided by contacting excess amounts of the COP or COP speciesin contact with water or an aqueous solution to provide a solutionsaturated with COP or a COP species. Such saturated solutions may thenbe diluted slightly, to afford a concentrate from which other COPspecies-containing compositions may be conveniently provided.

The compositions of the subject invention can be used in a variety ofadvantageous methods. For example, these compositions can be used in amethod which the compositions of the subject invention may furthercomprise one or more additional materials selected from the groupconsisting of: flavoring agents, colorants, viscosity modifiers,preservatives, fragrances, amino acids and their salts, vitamins,minerals, essential fatty acids, enzymes, co-enzymes, mono-glycerides,di-glycerides, tri-glyceride ester oils emulsifiers, hydrolyzedproteins, whey protein, stabilizers, flow modifiers, viscosityimprovers, chelating agents, anti-oxidants, anti-microbials, benzoates,alcohols, esters of para-hydroxybenzoic acid, propionates, preservativesand surfactants. Advantageously, these compositions are stable across awide range of pHs and temperatures.

The compositions of the subject invention can be formulated for avariety of modes of administration. These formulations include, but arenot limited to, compositions for oral administration, aqueous injectableformulations, injectable emulsion compositions, gel formulations, creamformulations, transdermal systems, transdermal patch systems, liquidbuccal sublingual solutions, oral solid compositions, and oral liquidcomposition with protein. The compositions of the subject invention canbe used in a variety of advantageous methods. For example, thesecompositions can be used in methods which cause regeneration of ADP toATP in muscle tissue, cause an increase in the serum concentration ofcreatine, cause an increase in the skeletal muscle concentrations ofcreatine and phosphocreatine (PCr), increase muscle fibersize/cross-sectional area and lean body mass, activate satellite cells,enhance memory and cognitive function, enhance the functional capacityof a mammal having a neuromuscular disease, increase muscular strength,endurance and/or power, enhance cognitive function in infants withinborn errors of creatine metabolism, or alleviate the deleteriouseffects of sleep deprivation.

Stability Study Materials and Methods

Creatinol-O-Phospate Solution: A batch of pure water or distilled wateris put in a container, adjusted to a prescribed of pH 3 or pH 7 with anormal buffer and buffer salts, and heated to a temperature of 20° to99° C. To 100 parts by weight of the warm water is added 0.1 to 0.3parts by weight of the Creatinol-O-Phophate (COP) which is dissolved bystirring. The pH is not particularly limited but is desirably not higherthan pH 12 taking the physiological influences of the gastrointestinaltracts into consideration.

Creatine Monohydrate Solution: Similarly, a batch of pure water ordistilled water is put in a container, adjusted to a prescribed of pH 3or pH 7 with a normal buffer and buffer salts, and heated to atemperature of 20° to 99° C. To 100 parts by weight of the warm water isadded 0.1 to 0.3 parts by weight of the Creatine Monohydrate (CM) whichis dissolved by stirring.

Disodium Creatine Phosphate Tetrahydrate Solution: Similarly, a batch ofpure water or distilled water is put in a container, adjusted to aprescribed or pH 3 or pH 7 with a normal buffer and buffer salts, andheated to a temperature of 20° to 99° C. To 100 parts by weight of thewarm water is added 0.1 to 0.3 parts by weight of the Disodium CreatinePhosphate Tetrahydrate (DCPT) which is dissolved by stirring.

The aqueous solutions of COP, CM, and DCPT were prepared at pH 3 and pH7 at a concentration of 0.250 mg/mL. They were stored at roomtemperature (25 C, 77 F), at refrigerator temperature (4 C, 39 F), andat elevated temperature (40 C, 104 F) in glass scintillation vials.These samples were assayed by HPLC at periodic intervals for 60 days andevaluated relative to Standard regression curves of known concentrationsof the actives and of creatinine, the primary known degradation productof creatine. The results are presented below:

-   Stability Study Results-   Preparation: Creatinol-O-Phosphate Aqueous Solution-   Concentration: 0.250 mg/mL-   pH: 7.0 Condition: 40° C.

Time Test INITIAL 3 day 10 days 21 days 39 Days 60 days Creatinol-O-0.226 mg/ml 0.229 mg/ml 0.238 mg/mL 0.236 mg/ml 0.258 mg/mL 0.230 mg/mLPhosphate Creatinine  0.0 mg/mL  0.0 mg/mL  0.0 mg/mL  0.0 mg/mL  0.00mg/mL  0.00 mg/mL pH 7.0 5.5 5.5

-   pH: 7.0 Condition: 25° C.

Time Test INITIAL 3 day 10 days 21 days 39 Days 60 days Creatinol-O-0.226 mg/ml 0.227 mg/ml 0.236 mg/mL 0.235 mg/ml 0.239 mg/mL 0.245 mg/mLPhosphate Creatinine  0.0 mg/mL  0.0 mg/mL  0.0 mg/mL  0.0 mg/mL  0.00mg/mL  0.00 mg/mL pH 7.0 5.3 5.3

-   pH: 7.0 Condition: 4° C.

Time Test INITIAL 3 day 10 days 21 days 39 Days 60 days Creatinol-O-0.226 mg/ml 0.228 mg/ml 0.237 mg/mL 0.238 mg/ml 0.244 mg/mL 0.247 mg/mLPhosphate Creatinine  0.0 mg/mL  0.0 mg/mL  0.0 mg/mL  0.0 mg/mL  0.00mg/mL  0.00 mg/mL pH 7.0 5.2 5.2

-   Preparation: Creatinol-O-Phosphate Aqueous Solution-   Concentration: 0.250 mg/mL-   pH: 3.0 Condition: 40° C.

Time Test INITIAL 3 day 10 days 21 days 39 Days 60 days Creatinol-O-0.247 mg/ml 0.235 mg/ml 0.239 mg/mL 0.239 mg/ml 0.241 mg/mL 0.273 mg/mLPhosphate Creatinine  0.0 mg/mL  0.0 mg/mL  0.0 mg/mL  0.0 mg/mL  0.00mg/mL  0.00 mg/mL pH 3.0 3.0 3.0

-   pH: 3.0 Condition: 25° C.

Time Test INITIAL 3 day 10 days 21 days 39 Days 60 days Creatinol-O-0.247 mg/ml 0.226 mg/ml 0.237 mg/mL 0.241 mg/ml 0.247 mg/mL 0.252 mg/mLPhosphate Creatinine  0.0 mg/mL  0.0 mg/mL  0.0 mg/mL  0.0 mg/mL  0.00mg/mL  0.00 mg/mL pH 3.0 3.1 3.1

-   pH: 3.0 Condition: 4° C.

Time Test INITIAL 3 day 10 days 21 days 39 Days 60 days Creatinol-O-0.247 mg/ml 0.232 mg/ml 0.243 mg/mL 0.245 mg/ml 0.249 mg/mL 0.250 mg/mLPhosphate Creatinine  0.0 mg/mL  0.0 mg/mL  0.0 mg/mL  0.0 mg/mL  0.00mg/mL  0.00 mg/mL pH 3.0 3.1 3.1

The Creatinol-O-Phosphate (COP) aqueous solutions of the subjectinvention remains stable after 60 days of storage at 4° C., 25° C. and40° C. at pH 3.0 and 7.0.

The data generated indicates that COP in aqueous solution is stable atroom temperature for normal warehouse storage conditions, stable at 104°F. (40 C degrees) for shipping in hot weather trucks and/or overseascontainers, and stable at 39° F. (4 C degrees) in coolers so that it canbe stored under refrigeration conditions.

-   Preparation: Creatine Monohydrate Aqueous Solution-   Concentration: 0.250 mg/mL-   pH: 7.0 Condition: 40° C.

Time Test INITIAL 3 day 39 Days 60 days Creatine Monohydrate 0.257 0.2420.251 0.200 mg/mL mg/ml mg/mL mg/mL Creatinine 0.000 0.008 0.068 0.101mg/mL mg/mL mg/mL mg/mL pH 7.0 7.4 7.4

-   Preparation: Creatine Monohydrate Aqueous Solution-   Concentration: 0.250 mg/mL-   pH: 3.0 Condition: 40° C.

Time Test INITIAL 3 day 10 days 21 days 39 Days 60 days Creatine 0.245mg/mL 0.091 mg/ml 0.036 mg/mL 0.029 mg/mL 0.030 mg/mL 0.020 mg/mLMonohydrate Creatinine 0.000 mg/mL 0.125 mg/Ml 0.177 mg/ml 0.186 mg/mL0.186 mg/mL 0.187 mg/mL pH 3.0 3.4 3.4

-   pH: 3.0 Condition: 25° C.

Time Test INITIAL 3 day 10 days 21 days 39 Days 60 days Creatine 0.245mg/mL 0.219 mg/ml 0.214 mg/mL 0.151 mg/mL 0.072 mg/mL 0.037 mg/mLMonohydrate Creatinine 0.000 mg/mL 0.026 mg/mL 0.072 mg/ml 0.111 mg/mL0.154 mg/mL 0.167 mg/mL pH 3.0 3.4 3.4

Creatine monohydrate in aqueous media show varying rates ofdecomposition to creatinine as well as other unknown compounds to anextent that 28% of creatine monohydrate converts to creatinine in 39days at pH 7.0 and 74% is converted to creatinine at pH 3.0 when storedat 40° C. And 62% of creatine monohydrate is converted to creatinine atpH 3.0 when stored at 4° C.

-   Preparation: Disodium Creatine Phosphate Tetrahydrate Aqueous    Solution-   Concentration: 0.250 mg/mL-   pH: 7.0 Condition: 40° C.

Time Test INITIAL 3 day 10 days 21 days 39 Days 60 days DisodiumCreatine 0.247 mg/mL 0.166 mg/ml 0.066 mg/mL 0.015 mg/mL 0.002 mg/mL 0.00 mg/mL Phosphate Tetrahydrate Creatine  0.00 mg/mL 0.042 mg/mL0.114 mg/mL 0.122 mg/mL 0.108 mg/mL 0.098 mg/mL Monohydrate Creatinine0.000 mg/mL 0.004 mg/mL 0.012 mg/mL 0.020 mg/ml 0.030 mg/mL 0.035 mg/mLpH 7.0 7.8 7.8

-   pH: 7.0 Condition: 25° C.

Time Test INITIAL 3 day 10 days 21 days 39 Days 60 days DisodiumCreatine 0.247 mg/mL  0.229 mg/ml 0.231 mg/mL 0.182 mg/mL 0.141 mg/mL0.140 mg/mL Phosphate Tetrahydrate Creatine  0.00 mg/mL 0.0.14 mg/mL0.041 mg/mL 0.069 mg/mL 0.089 mg/mL 0.094 mg/mL Monohydrate Creatinine0.000 mg/mL  0.000 mg/mL 0.000 mg/mL 0.000 mg/ml 0.000 mg/mL 0.000 mg/mLpH 7.0 7.8 7.8

It can be seen from the data above that DCPT solution at pH 7 convertsto creatine monohydrate at 40 C and 25 C.

However, the newly formed creatine monohydrate (CM) starts to degrade tocreatinine. This can be seen in the data at 40 C above where there is agradual increase in the formation of CM up to the 21-day test to 0.188mg/mL but then a decrease of CM at the 39-day test down to 0.108 mg/mL.

The mechanism for the conversion of DCPT to CM has not been elucidatedbut it is believed to be due to the hydrolysis of ester linkage of DCTPto yield free Creatine and inorganic phosphate.

-   Preparation: Disodium Creatine Phosphate Tetrahydrate Aqueous    Solution-   Concentration: 0.250 mg/mL-   pH: 3.0 Condition: 40° C.

Time Test INITIAL 3 day 10 days 21 days 39 Days 60 days Disodium 0.247mg/mL 0.000 mg/ml 0.000 mg/mL 0.000 mg/mL 0.000 mg/mL  0.00 mg/mLCreatine Phosphate Tetrahydrate Creatine 0.004 mg/mL 0.042 mg/mL 0.017mg/mL 0.011 mg/mL 0.012 mg/mL 0.012 mg/mL Monohydrate Creatinine 0.000mg/mL 0.054 mg/mL 0.086 mg/mL 0.080 mg/ml 0.081 mg/mL 0.086 mg/mL pH 3.03.4 3.4

-   pH: 3.0 Condition: 25° C.

Time Test INITIAL 3 day 10 days 21 days 39 Days 60 days Disodium 0.247mg/mL 0.000 mg/ml 0.000 mg/mL 0.000 mg/mL  0.00 mg/ml  0.00 mg/mLCreatine Phosphate Tetrahydrate Creatine 0.000 mg/ml 0.095 mg/mL 0.092mg/mL 0.065 mg/mL 0.031 mg/mL 0.013 mg/mL Monohydrate Creatinine 0.000mg/mL 0.014 mg/mL 0.034 mg/mL 0.050 mg/ml 0.069 mg/mL 0.075 mg/mL pH 3.03.4 3.4

It can be seen from the data above that DCPT solution at pH 3 convertsto creatine monohydrate at 40 C and 25 C.

However, the newly formed creatine monohydrate (CM) starts to degrade tocreatinine. This can be seen in the data at 40 C and 25 C above where,in both cases, there is an increase in the formation of CM from theinitial test to the 3-day test followed by a decrease of CM starting atthe 10-day test.

Disodium Creatine Phosphate Tetrahydrate in aqueous media show varyingrates of decomposition to creatinine as well as other unknown compounds.Disodium creatine phosphate tetrahydrate degrades rapidly (in less than3 days) and converts to creatine monohydrate. The data showing thisconversion is presented in the tables above. The newly formed creatinemonohydrate then degrades to creatinine.

The mechanism for the conversion of disodium creatine phosphatetetrahydrate to creatine monohydrate has not been elucidated but it isbelieved to be due to the hydrolysis of ester linkage of disodiumcreatine phosphate tetrahydrate to yield free creatine and inorganicphosphate. The mechanism of hydrolysis may be affected by the ionizationof the phosphate group (pKa1=2 and pKa2=6.2).

Following are examples which illustrate procedures for practicing theinvention. These examples should not be construed as limiting. Allpercentages are by weight and all solvent mixture proportions are byvolume unless otherwise noted.

EXAMPLE 1 Aqueous Injectable Formulations

One embodiment of the subject invention is an aqueous injectablecomposition. This composition is isotonic and sterile, and comprisesCreatinol-O-Phosphate (COP). Preferably, the COP injectable preparationhas a pH of about 3, and is substantially stable at room temperature fornormal warehouse storage conditions, stable at 104° F. (40 C degrees)for shipping in hot weather trucks and/or overseas containers, andstable at 39° F. (4 C degrees) in coolers so that it can be stored underrefrigeration conditions.

The composition can comprise a suitable aqueous solvent, and one or morepreservatives, physical stabilizing ingredients and one or more buffersthat can render the composition pH stable.

The composition may also contain nucleotides, oligonucleotides,monophosphates, diphosphates, triphosphates (and cyclic derivatives ofthese nucleotides), and amino acids, peptides, proteins andcarbohydrates.

-   Specific Aqueous Injectable Formulations:-   Formulation I

Ingredient % w/v COP 2.10 AMP 12.5 UTP 0.10 Amino Acids 3.0-7.0Polysorbate 80 0.40 Sodium CMC 0.50 Sodium Chloride 0.90 Benzyl alcohol0.90 Buffer Salt(s) QS to adjust to desired pH Sodium Hydroxide QS toadjust to desired pH Water for Injection QS to 100

-   Formulation II

Ingredient % w/v COP 2.10 AMP 12.50 UTP 0.10 Amino Acids 3.0-7.0Polysorbate 80 0.40 Sorbitol 40.00 Sodium Chloride 0.90 Benzyl alcohol0.90 Buffer Sat(s) QS to adjust to desired pH Sodium Hydroxide QS toadjust to desired pH Water for Injection QS to 100

-   Formulation III

Ingredient % w/v COP 2.10 Polysorbate 80 0.40 AMP 12.50 UTP 0.10 AminoAcids 3.0-7.0 Sodium Citrate 0.50 Sodium Chloride 0.90 Benzyl alcohol0.90 Buffer Salt(s) QS to adjust to desired pH Sodium Hydroxide QS toadjust to desired pH Water for Injection QS to 100

EXAMPLE 2 Injectable Emulsion Composition

One embodiment of the subject invention is an injectable emulsioncomposition for human use. This composition is isotonic and sterile, andcomprises Creatinol-O-Phosphate (COP). Preferably, the COP preparationhas a pH of about 3, and is substantially stable at room temperature fornormal warehouse storage conditions, stable at 104° F. (40 C degrees)for shipping in hot weather trucks and/or overseas containers, andstable at 39° F. (4 C degrees in coolers so that it can be stored underrefrigeration conditions.

The composition can comprise a suitable aqueous solvent, apharmaceutically acceptable oil (sesame, olive, castor, peanut, cottonseed, etc.), natural emulsifiers such as lecithin or any other syntheticemulsifier, be it of the polysorbate or ethoxylated glyceride type, oneor more preservatives, physical stabilizing ingredients and one or morebuffer salts that can render the composition pH stable.

The composition may also contain nucleotides, oligonucleotides,monophosphates, diphosphates, triphosphates (and cyclic derivatives ofthese nucleotides), and amino acids, peptides, proteins andcarbohydrates.

-   Specific Injectable Emulsion Formulations:-   Formulation I

Ingredient % w/v COP 2.10 AMP 12.5 UTP 0.10 Amino Acids 3.0-7.0 SesameOil  2.0-12.0 Polysorbate 80 0.40 Sodium Chloride 0.90 Benzyl alcohol0.90 Buffer Salt(s) QS to adjust to desired pH Sodium Hydroxide QS toadjust to desired pH Water for Injection QS to 100

-   Formulation II

Ingredient % w/v COP 2.10 AMP 12.50 UTP 0.10 Amino Acids 3.0-7.0 OliveOil  1.0-15.0 Lecithin 0.50-5.0  Sorbitol 30.00 Sodium Chloride 0.90Benzyl alcohol 0.90 Buffer Sat(s) QS to adjust to desired pH SodiumHydroxide QS to adjust to desired pH Water for Injection QS to 100

-   Formulation III

Ingredient % w/v COP 2.10 Peanut Oil 1.0-15.0 Polysorbate 80 0.2-10.0AMP 12.50 UTP 0.10 Amino Acids 3.0-7.0  Sodium Citrate 0.50 SodiumChloride 0.90 Benzyl alcohol 0.90 Buffer Salt(s) QS to adjust to desiredpH Sodium Hydroxide QS to adjust to desired pH Water for Injection QS to100

EXAMPLE 3 Gel Formulation

One embodiment of the subject invention is a gel topical composition forskin application. This composition is clear or slightly opaque and has agel consistency so that it can be spread on a skin surface. Thecomposition comprises COP and has a pH of about 3 to 7. The compositionis substantially stable at room temperature for normal warehouse storageconditions, stable at 104° F. (40 C degrees) for shipping in hot weathertrucks and/or overseas containers, and stable at 39° F. (4 C degrees) incoolers so that it can be stored under refrigeration conditions. Thecomposition can comprise a suitable aqueous solvent, preservatives,polymers for imparting consistency, physical stabilizing ingredients andone or more buffers that can render the composition pH stable.

The composition may also contain nucleotides, oligonucleotides,monophosphates, diphosphates, triphosphates (and cyclic derivatives ofthese nucleotides), and amino acids, peptides, proteins andcarbohydrates.

-   Specific Gel Formulations:-   Formulation I

INGREDIENTS % w/w COP 2.10 Peptides/Polypeptides 3.00 AMP 12.50 UTP 0.10Ubiquinone 3.20 Propylene Glycol 12.0 Carbomer 1.00 Buffer Salt(s) QS todesired pH Methylparaben 0.20 Propylparaben 0.10 Purified Water QS to100

-   Formulation II

INGREDIENTS % w/w COP 2.10 Peptides/Polypepetides 3.00 AMP 12.50 UTP0.10 Ubiquinone 3.20 Glycerin 5.00 Hydroxyethylcellulose 2.00Trietanolamine QS to desired pH Methylparaben 0.20 Propylparaben 0.10Purified Water QS to 100

-   Formulation III

INGREDIENTS % w/w COP 2.10 Peptides/Polypepetides 3.00 AMP 12.50 UTP0.10 Ubiquinone 3.20 Glycerin 15.0 Poloxamers 407/188 10.00Triethanolamine QS to desired pH Methylparaben 0.025 Propylparaben 0.015Purified Water QS to 100

EXAMPLE 4 Cream Formulations

One embodiment of the subject invention is a cream topical compositionfor skin application. This composition is an emulsion system or anopacified gel system and has a cream consistency so that it can bespread on a skin surface. The composition comprises COP and has a pH ofabout 3 to 7. The composition is substantially stable at roomtemperature for normal warehouse storage conditions, stable at 104° F.(40 C degrees) for shipping in hot weather trucks and/or overseascontainers, and stable at 39° F. (4 C degrees) in coolers so that it canbe stored under refrigeration conditions.

The composition can comprise a suitable aqueous solvent, preservatives,physical stabilizing ingredients, surfactants, moisturizers, and one ormore buffers salt that can render the composition pH stable.

The composition may also contain nucleotides, oligonucleotides,monophosphates, diphosphates, triphosphates (and cyclic derivatives ofthese nucleotides), and amino acids, peptides, proteins andcarbohydrates.

Specific Cream Formulations:

Formulation I

INGREDIENTS % w/w COP 2.10 White Petrolatum 20.0 Stearyl Alcohol 20.0Propylene Glycol 12.0 Peptides/Polypeptides 3.00 AMP 12.50 UTP 0.10Ubiquinone 3.20 Sodium lauryl Sulfate 1.00 Methylparaben 0.20Propylparaben 0.10 Buffer Salt(s) QS to adjust pH Purified Water QS to100Formulation II

INGREDIENTS % w/w COP 2.10 Peptides/Polypeptides 3.00 AMP 12.50 UTP 0.10Ubiquinone 3.20 Mineral Oil 15.0 Lanolin Alcohol 10.0 Cetyl Alcohol 0.20Beeswax 4.00 Sorbitan Monoleate 5.00 Glycerin 5.00 Borax 0.30Trietanolamine 0.70 Methylparaben 0.20 Propylparaben 0.10 Buffer Salt(s)QS to adjust pH Purified Water QS to 100Formulation III

INGREDIENTS % w/w COP 2.10 Peptides/Polypeptides 3.00 AMP 12.50 UTP 0.10Ubiquinone 3.20 Glyceryl Monostearate 10.0 Lanolin 2.00 Glycerin 10.0Stearyl Pyridinium Chloride 1.50 Methylparaben 0.025 Propylparaben 0.015Buffer Salt(s) QS to adjust pH Purified Water QS to 100

EXAMPLE 5 Transdermal Systems

One embodiment of the subject invention is a deep-penetratingtransdermal composition. This composition can be a solution, a gel-likeor an emulsion-like system or an opacified gel-like system having aconsistency so that it can be spread on skin surface. The compositioncomprises COP which is substantially stable at room temperature fornormal warehouse storage conditions, stable at 104° F. (40 C degrees)for shipping in hot weather trucks and/or overseas containers, andstable at 39° F. (4 C degrees) in coolers so that it can be stored underrefrigeration conditions.

The composition can comprise suitable aqueous solvents, non-aqueoussolvents, one or more penetrating enhancers, preservatives, physicalstabilizing ingredients, surfactants, moisturizers, and buffers that canrender the composition pH stable.

The composition may also contain nucleotides, oligonucleotides,monophosphates, diphosphates, triphosphates (and cyclic derivatives ofthese nucleotides), and amino acids, peptides, proteins andcarbohydrates.

-   Specific Transdermal Systems:-   System I

INGREDIENTS % w/w COP 2.10 N-methylpyrrolidone 15.0 Peptides 3.00 AMP12.50 UTP 0.10 Ubiquinone 3.20 Alcohol USP 2.00 Benzyl alcohol 1.00Buffer Salt(s) QS to adjust pH Purified Water QS to 100

-   System II

INGREDIENTS % w/w COP 2.10 Peptides 3.00 AMP 12.50 UTP 0.10 Ubiquinone3.20 Ethoxydiglycol 25.0 Alcohol USP 2.00 PEG esters and monoglycerides15.0 Benzyl alcohol 1.00 Buffer Salt(s) QS to adjust pH Purified WaterQS to 100

-   System III

INGREDIENTS % w/w COP 2.10 Peptides 3.00 AMP 12.50 UTP 0.10 Ubiquinone3.20 Propylene Glycol 25.0 Alcohol USP 4.00 Polysorbate 80 10.0 Benzylalcohol 1.00 Buffer Salt(s) QS to adjust pH Purified Water QS to 100

EXAMPLE 6 Transdermal Patch Systems

One embodiment of the subject invention is a transdermal patch deliverysystem. The system can comprise a liner, an adhesive, backing and anaqueous liquid reservoir composition. The aqueous liquid reservoircomposition being a solution or a suspension comprising COP. The COP issubstantially stable at room temperature for normal warehouse storageconditions, stable at 104° F. (40 C degrees) for shipping in hot weathertrucks and/or overseas containers, and stable at 39° F. (4 C degrees) incoolers so that it can be stored under refrigeration conditions.

The composition can comprise a suitable aqueous solvent, non-aqueoussolvent(s), one or more penetrating enhancers, preservatives, physicalstabilizing ingredients, surfactants, buffer salts that can render thecomposition pH stable.

The composition may also contain nucleotides, oligonucleotides,monophosphates, diphosphates, triphosphates (and cyclic derivatives ofthese nucleotides), and amino acids, peptides, proteins andcarbohydrates.

-   Specific Liquid Reservoir for Transdermal Patch:-   Formulation I

INGREDIENTS % w/w COP 5.00 N-methylpyrrolidone 10.0 Peptides 3.00 AMP12.50 UTP 0.10 Ubiquinone 3.20 Alcohol USP 45.0 Benzyl alcohol 1.00Buffer Salt(s) QS to adjust pH Purified Water QS to 100

-   Formulation II

INGREDIENTS % w/w COP 5.00 Peptides 3.00 AMP 12.50 UTP 0.10 Ubiquinone3.20 Ethoxydiglycol 20.0 Alcohol USP 50.0 Benzyl alcohol 1.00 BufferSalt(s) QS to adjust pH Purified Water QS to 100

-   Formulation III

INGREDIENTS % w/w COP 5.00 Peptides 3.00 AMP 12.50 UTP 0.10 Ubiquinone3.20 Propylene Glycol 20.0 Alcohol USP 40.0 Polysorbate 80 5.0 Benzylalcohol 1.00 Buffer Salt(s) QS to adjust pH Purified Water QS to 100

EXAMPLE 7 Liquid Buccal Sublingual Solution

One embodiment of the subject invention is an oral liquid compositionfor buccal sublingual administration. The composition can comprise COPand have a pH of about 3 to 7. The composition is being substantiallystable at room temperature for normal warehouse storage conditions,stable at 104° F. (40 C degrees) for shipping in hot weather trucksand/or overseas containers, and stable at 39° F. (4 C degrees) incoolers so that it can be stored under refrigeration conditions.

The composition can comprise a suitable aqueous solvent or vehicle, anon-aqueous vehicle, preservatives, physical stabilizing ingredients,surfactants, and buffer salts that can render the composition pH stable.

The composition may also contain nucleotides, oligonucleotides, themonophosphates, diphosphates, triphosphates (and cyclic derivatives ofthese nucleotides), amino acids, vitamins and vitamin-like isoprenoids,peptides and one or more additional components selected from lipids,starches, carbohydrates, polyols, minerals, electrolytes, amino traceelements, colorings, flavors, artificial sweeteners, and anti-oxidants.

-   Specific Liquid Buccal Sublingual Solutions:

EXAMPLE I

INGREDIENTS % w/w COP 2.10 N-methylpyrrolidone 10.0 Peptides 3.00 AMP12.50 UTP 0.10 Ubiquinone 3.20 Alcohol USP 45.0 Benzyl alcohol 1.00Buffer Salt(s) QS to adjust pH Purified Water QS to 100

EXAMPLE II

INGREDIENTS % w/w COP 2.10 Peptides 3.00 AMP 12.50 UTP 0.10 Ubiquinone3.20 Ethoxydiglycol 20.0 Alcohol USP 50.0 Benzyl alcohol 1.00 BufferSalt(s) QS to adjust pH Purified Water QS to 100

EXAMPLE III

INGREDIENTS % w/w COP 2.10 Peptides 3.00 AMP 12.50 UTP 0.10 Ubiquinone3.20 Propylene Glycol 20.0 Alcohol USP 40.0 Polysorbate 80 5.0 Benzylalcohol 1.00 Buffer Salt(s) QS to adjust pH Purified Water QS to 100

EXAMPLE 8 Oral Solid Compositions

One embodiment of the subject invention is an oral solid composition inthe form of a capsule (e.g. LiCap®) with a liquid composition as fillmaterial containing from about 1% to about 20% of water. The liquid fillmaterial has a pH of about 3 to 7 and is substantially stable at roomtemperature for normal warehouse storage conditions, stable at 104° F.(40 C degrees) for shipping in hot weather trucks and/or overseascontainers, and stable at 39° F. (4 C degrees) in coolers so that it canbe stored under refrigeration conditions.

The composition can comprise a suitable lipophilic solvent or vehicle, ahydrophilic non-aqueous vehicle, from about 1% to about 20% of water,preservatives, physical stabilizing ingredients, surfactants, and buffersalts that can render the composition pH stable.

The composition may also contain nucleotides, oligonucleotides, themonophosphates, diphosphates, triphosphates (and cyclic derivatives ofthese nucleotides), amino acids, vitamins and vitamin-like isoprenoids,peptides and one or more additional components selected from lipids,medium and short chain triglycerides, starches, polyols, carbohydrates,minerals, electrolytes, amino trace elements, colorings, andanti-oxidants.

-   Specific Fill Material Composition for Capsule:

EXAMPLE I

INGREDIENTS % w/w COP 2.10 Medium chain triglyceride 15.0 Peptides 3.00AMP 12.50 UTP 0.10 Ubiquinone 3.30 Oleic Acid 52.0 Benzyl alcohol 1.00Purified Water 1.0-10.0

EXAMPLE II

INGREDIENTS % w/w COP 2.10 Peptides 3.00 AMP 12.50 UTP 0.10 Ubiquinone3.30 Polysorbate 80 25.0 PEG-40 Hydrogenated Castor Oil 38.00 PEG estersand monoglycerides 15.0 Benzyl alcohol 1.00 Purified Water QS to 100

EXAMPLE III

INGREDIENTS % w/w COP 2.10 Peptides 3.00 AMP 12.50 UTP 0.10 Ubiquinone3.30 PEG-400 45.0 PEG esters and monoglycerides 9.00 Polysorbate 80 20.0Benzyl alcohol 1.00 Buffer Salt(s) QS to adjust pH Purified Water QS to100

EXAMPLE 9 Oral Liquid Composition with Protein

One embodiment of the subject invention is an oral liquid compositioncontaining from 1 gram to 100 grams of protein and from 1 gram to 100grams of carbohydrates per serving and further comprising COP. The COPis stable at room temperature for normal warehouse storage conditions,stable at 104° F. (40 C degrees) for shipping in hot weather trucksand/or overseas containers, and stable at 39° F. (4 C degrees) incoolers so that it can be stored under refrigeration conditions.

The composition can comprise acid stable protein isolates, or acombination or blend of protein isolates, concentrates and hydrolyzates,and caseins in micellar forms, a suitable aqueous solvent or vehicle, anon-aqueous vehicle, preservatives, physical stabilizing ingredients,surfactants, and buffer salts that can render the composition pH stable.

The composition may also contain nucleotides, oligonucleotides, themonophosphates, diphosphates, triphosphates (and cyclic derivatives ofthese nucleotides), amino acids, vitamins and vitamin-like isoprenoids,peptides and one or more additional components selected from lipids,starches, carbohydrates, polyols, minerals, electrolytes, amino traceelements, colorings, flavors, artificial sweeteners, and anti-oxidants.

-   High pH RTD Protein Blend Formulations

Ingredient % w/w Per 16 oz Serving COP 1.00 2.10 Whey Protein Isolate6.000 30.00 Whey Protein Concentrate 0.640 3.20 Whey Hydrolysate 0.3201.60 Micellar casein 0.320 1.60 Casein Protein Hydrolysate 0.000 0.00Potassium Chloride 0.076 0.38 Ascorbic Acid 0.012 0.06 Vitamin E TPGS0.052 0.26 Riboflavin 100 0.000 0.00000010 Niacin 0.000 0.0020Pyrodoxine HCl 0.000 0.000007 Calcium Panthothenate 0.000 0.0011Magnesium Maleate 0.020 0.1000 d-ribose 0.040 0.2000 Centromix E 0.6003.00 Saflower Oil 1.200 6.00 Sunflower Oil 1.200 6.00 Medium ChainTriglycerides 0.800 4.00 L-Glutamine 0.025 0.13 Glucose Polymers (Ricetrin) 0.800 4.00 Waxy Maize Starch 1.000 5.00 High Amylose Starch(Amylose ADP11P) 0.100 0.50 Magnessium Citrate 0.124 0.62Microcrystalline Cellulose 0.100 0.50 Malic Acid 0.140 0.70 Citric acid0.566 2.83 Sodium Citrate 0.140 0.70 Sucralose 0.011 0.06 Glycerine3.000 15.00 Na 2 EDTA 0.050 0.25 Sodium Benzoate 0.090 0.45 PotassiumSorbate 0.190 0.95 Water QS QS TOTAL 100 500.0

-   Low pH RTD Protein Formulations

Ingredient Per 16 oz serving % w/w COP 2.10 0.25 Whey Protein IsolateAcid Stable 44.44 9.26 Sucralose 0.12 0.025 Na EDTA 0.24 0.050 PotassiumSorbate 0.96 0.200 Sodium Benzoate 0.48 0.100 Citric Acid to pH 3.0 QSQS Malic Acid to pH 3.0 QS QS Water 433.8 90.37 Total 480 100

-   Low pH RTD Protein Formulations

Ingredient Per 16 oz serving % w/w COP 2.10 0.25 Whey Protein IsolateAcid Stable 44.44 9.26 Sucralose 0.12 0.025 Waxy Maize Starch 4.80 1.00Glucose Polymers (Rice trin) 0.96 0.20 Na EDTA 0.24 0.050 PotassiumSorbate 0.96 0.200 Sodium Benzoate 0.48 0.100 Citric Acid to pH 3.0 QSQS Malic Acid to pH 3.0 QS QS Water QS QS Total 480 100

Although this invention has been described and disclosed in relation tocertain preferred embodiments, obvious equivalent modifications andalterations thereof will become apparent to one of ordinary skill inthis art upon reading and understanding this specification and theclaims appended hereto. This includes subject matter defined by anycombination of any one of the various claims appended hereto with anyone or more of the remaining claims, including the incorporation of thefeatures and/or limitations of any dependent claim, singly or incombination with features and/or limitations of any one or more of theother dependent claims, with features and/or limitations of any one ormore of the independent claims, with the remaining dependent claims intheir original text being read and applied to any independent claims somodified. This also includes combination of the features and/orlimitations of one or more of the independent claims with featuresand/or limitations of another independent claims to arrive at a modifiedindependent claim, with the remaining dependent claims in their originaltext being read and applied to any independent claim so modified.Accordingly, the present disclosure is intended to cover all suchmodifications and alterations and is not intended to be necessarilylimited by any one or more particular strict interpretations of theclaims which now follow.

What is claimed is:
 1. A method for providing a biologically-active formof creatine to a mammal via administration of an aqueous composition,wherein said method comprises: a) storing an aqueous compositioncomprising at least one creatinol-O-phosphate species and water; b)administering said aqueous composition to a mammal using a transdermalsystem.
 2. The method according to claim 1, wherein said aqueouscomposition further comprises one or more ions selected from the groupconsisting of sodium, potassium, zinc, calcium, and magnesium.
 3. Themethod according to claim 1, wherein said aqueous composition furthercomprises one or more additional materials selected from the groupconsisting of: flavoring agents, colorants, viscosity modifiers,preservatives, fragrances, amino acids and their salts, vitamins,minerals, essential fatty acids, enzymes, co-enzymes, mono-glycerides,di-glycerides, tri-glyceride ester oils emulsifiers, hydrolyzedproteins, whey protein, stabilizers, flow modifiers, viscosityimprovers, chelating agents, anti-oxidants, anti-microbials, benzoates,alcohols, esters of para-hydroxybenzoic acid, propionates, preservativesand surfactants.
 4. The method according to claim 1, wherein saidaqueous composition further comprises a preservative present in aneffective amount to inhibit microbial growth.
 5. The method according toclaim 1, wherein said aqueous composition comprises at least one anionhaving a structure selected from the group consisting of:

(including zwitterionic forms thereof).
 6. The method of claim 1,wherein the composition is in the form of a gel formulation.
 7. Themethod of claim 6, wherein the gel formulation further comprises one ormore polymers for imparting consistency, one or more physicalstabilizing ingredients and one or more buffers that render thecomposition pH stable.
 8. The method of claim 7, wherein the gelformulation further comprises one or more of carbomer,hydroxyethylcellulose, methylbaraben, and propylparaben.
 9. The methodclaim 1, wherein the composition is in the form of a cream formulation.10. The method of claim 9, wherein the cream formulation furthercomprises one or more of white petrolatum, propylene glycol,methylparaben.
 11. The method of claim 1, wherein the transdermal systemis a transdermal patch.
 12. The method of claim 11 wherein thetransdermal patch comprises a liner, an adhesive, backing and an aqueousliquid reservoir.